Gentisic acid has been disclosed as a stabiliser for use in lyophilised kits for the preparation of 99mTc diphosphonic acid radiopharmaceuticals [Tofe et al, J. Nucl. Med., 21, 366-370 (1980)]. U.S. Pat. No. 4,233,284 and U.S. Pat. No. 4,497,744 disclose similar subject matter.
U.S. Pat. No. 5,384,113 discloses that gentisic acid, gentisyl alcohol and water soluble salts, esters and mixtures thereof are useful to prevent autoradiolysis of peptides radiolabelled with 111In, 67Ga, 169Yb, 125I, 123I or 201Tl. Examples 1 to 7 of U.S. Pat. No. 5,384,113 refer to 111In-labelled peptides, and Example 9 to a 186Re-labelled peptide. Example 8 describes the preparation of 123I-labelled LH-RH (luteinizing hormone releasing factor). Example 8 does not, however, does not include any evidence that gentisic acid is an effective stabiliser for 123I-LH-RH.
U.S. Pat. No. 6,315,979 discloses radioiodinated phenol derivatives of the formula shown for use as renal function imaging radiopharmaceuticals and in brachytherapy:
where: m and n are independently 0, 1, 2 or 3;
X is a group that is negatively or positively charged at physiological pH;R, R1, R2 and R3 are independently H or C1-4 alkyl; andI* is 123I, 131I or 125I.
U.S. Pat. No. 6,315,979 discloses that the radioiodinated phenols may potentially be stabilised with a variety of stabilisers chosen from: benzyl alcohol, ascorbic acid, gentisic acid, cysteine, butylated hydroxytoluene (BHT), citric acid, human serum albumin (HSA), glycerol, cysteamine, sulfarem, glutathione, tryptophan and iodoacetamide. No specific disclosure is made on the use of gentisic acid to stabilise radioiodinated phenols.
WO 02/04030 discloses pharmaceutical compositions comprising a radiolabelled pharmaceutical agent labelled with a radioisotope chosen from: 99mTc, 131I, 125I, 123I, 117mSn, 111In, 97Ru, 203Pb, 67Ga, 68Ga, 89Zr, 90Y, 177Lu, 149Pm, 153Sm, 166Ho, 32P, 211At, 47SC, 109Pd, 105Rh, 186Re, 188Re, 60Cu, 62Cu, 64Cu and 67Cu; stabilised with a compound of formula:
where E1 is NH2 or OH; A1, A2, A3, A4 and A5 are each independently N, C(OH) or CR1; provided that at least one of A1, A2, A3, A4 and A5 is not CH; each R1 is independently H, C(O)R2, C(O)OR2, NHC(═O)NHR2, NHC(═S)NHR2, OC(═O)R2, OC(═O)OR2, S(O)2OR2, C(O)NR3R4, C(O)NR3OR4, C(O)NR2NR3R4, NR3R4, NR3C(O)R4, PO(OR3)(OR4), S(O)2NR3R4, S(O)2NR2NR3R4, S(O)2NR3OR4, C1-C10 alkyl substituted with 0-5 R5, C3-C10 cycloalkyl substituted with 0-5 R5, C2-C10 alkenyl substituted with 0-5 R5, or aryl substituted with 0-5 R5; R2, R3, and R4 are each independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkenyl, benzyl, or phenyl; or R3 and R4 together form C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally interrupted with O, S, NH, S(═O), S(O)2, P(═O)(OH), C(═O)NH, NHC(═O), NH(C═O)NH, or NH(C═S)NH; and each R5 is independently H, NH2, OH, CO2H, C(═O)NH2, C(═O)NHOH, C(═O)NHNH2, NH(C═NH)NH2, NH(C═O)NH2, NH(C═S)NH2, PO3H2, SO3H, or S(O)2NH2; or a pharmaceutically acceptable salt thereof.
WO 02/04030 does not seem to define A6. The term “non-peptide” is defined very broadly to be a compound having less than 3 amide bonds in the backbone or less than 3 amino acids. The specification states that the stabiliser is preferably not gentisic acid. No specific disclosure is made on the use of gentisic acid as a stabiliser for radioiodine radiopharmaceuticals.
Mallinckrodt sell an 123I-labelled meta-iodobenzylguanidine radiopharmaceutical product [MIBG (I-123) Injection] which contains gentisic acid at a concentration of approximately 0.5 mg/ml. The pH of the preparation is 4.0±0.5.
Eersels et al [J. Lab. Comp. Radiopharm., 48, 241-257 (2005)], review methods of manufacturing 123I-labelled radiopharmaceuticals. At page 254 they mention that acidic conditions (pH 3-4 buffer) are advisable to minimise deiodination during autoclaving, but that for some compounds it is necessary to also employ a radical scavenger to suppress deiodination. Classical radical scavengers such as ascorbic acid or gentisic acid are said to be often omitted during autoclaving due to their colouration. The radical scavengers thiourea, N-acetylcysteine and ortho-iodohippuric acid (OIH) are said to give satisfactory results in stabilising a specific compound (123I-R91150) against radiolysis, but of these only OIH was viewed as being suitable for use in a composition for intravenous human injection (pages 254-55).